Retinoids, the natural metabolites and synthetic analogues of vitamin A (retinol), are important regulators of skin function. Fisher, et al., Faseb J 1996; 10: 1002-13. All-trans-retinoic acid (vitamin A acid), the major naturally occurring biologically active retinoid, has been a focus of research for possible use in topical treatments for photodamaged skin, for many years. In 1986, it was reported that retinoic acid could produce smoother, less wrinkled, and less pigmented skin after a few months of treatment. Kligman et al., J Am Acad Dermatol 1986; 15: 836-59.
Long-term exposure of skin to sunlight leads to a series of progressive changes that range from loss of skin texture and tone to thinning of the epidermis and stratum corneum (Gilchrest, Br J Dermatol 1996; 135: 867-75), flattening of the dermal-epidermal junction (Benedetto, Clin Dermatol 1998; 16: 129-39), generation of areas of hyperpigmentation (Gilchrest, supra), wrinkles, and accumulation of keratinocytes with atypical morphology that are likely precursors to actinic keratoses and non melanoma skin cancers (Cho, et al., J Am Acad Dermatol 2005; 53: 769-74; Lober, et al., J Am Acad Dermatol 2000; 43: 881-2). Photodamage occurs in both the epidermal and dermal compartments, where retinoids have been shown to have prominent pharmacological effects. Gendimenico, et al., Skin Pharmacol 1993; 6 Suppl 1: 24-34; Varani, et al., J Invest Dermatol 2000; 114: 480-6; Cho, et al., supra. In the epidermis of photodamaged skin, long-term topical retinoid therapy results in dose dependent increases in epidermal and granular layer thickness, stratum corneum compaction, decreased melanin content and improvement of epidermal atypia. Fisher et al., supra; Cho, et al., supra; Olsen, et al., J Am Acad Dermatol 1992; 26: 215-24; Machtinger, et al., Br J Dermatol 2004; 151: 1245-52. In keratinocytes, retinoids induce proliferation, presumably mediated by epidermal growth factor receptor activation resulting in epidermal hyperplasia. Rittie, et al., J Invest Dermatol 2006; 126: 732-9.
Retinoic acid induced expression of keratins K6, K16, and K17, which are commonly expressed in hyperproliferative epidermal cells, indicates that retinoids increase cell proliferation in the basal and/or lower spinous layers of the epidermis. Eichner, et al., Br J Dermatol 1996; 135: 687-95. Retinoids also can lighten hyperpigmented skin, reduce tyrosinase activity in cultured melanocytic cells (Hoal, et al., Cancer Res 1982; 42: 5191-5; Kang, et al., Am J Clin Dermatol 2005; 6: 245-53), inhibit proliferation and lipid synthesis, and alter keratin expression in cultured human sebocytes. Zouboulis, et al., J Invest Dermatol 1991; 96: 792-7. In the dermis, effects include increased fibroblast proliferation (Varani, et al., supra), increased collagen production (Griffiths, et al., N Engl J Med 1993; 329: 530-5), and reduced extracellular matrix degradation (Fisher and Voorhees, supra).
The degradation of collagen in the dermis is a major factor in the formation of skin wrinkles. Prolonged use of retinoic acid significantly increases collagen matrix deposition in dermal repair zones and this effect appears to be responsible for the wrinkle reduction that accompanies retinoic acid treatment of photodamaged skin. (Cho, et al., supra; Kang, et al., supra).
While retinoic acid provides multiple benefits to photodamaged skin (Kang, et al., supra), it is frequently accompanied by significant skin irritation that limits compliance with therapy. Lowe, et al., J Cosmet Laser Ther 2004; 6: 79-85. The most commonly reported retinoic acid treatment-related adverse effects are irritation, dryness, peeling, erythema, and a sensation of burning on the skin. Lowe, et al., supra. These side effects often result in discontinuation of therapy.
Hence, a method to diminish or eliminate the side effects associated with retinoic acid therapy is needed.
The mechanisms that lead to retinoid side effects are still incompletely understood but retinoic acid therapy is known to impair stratum corneum barrier function as assessed by TEWL measurements. Tagami, et al., Br J Dermatol 1992; 127: 470-5. Barrier impairment has been attributed to retinoid-induced epidermal hyperplasia (Varani, et al., Arch Dermatol Res 2003; 295: 255-62) and to alteration of the terminal differentiation program (Fisher, et al., supra). Erythema, which reflects the production of epidermal cytokines such as IL-1, may result from retinoid-stimulated keratinocyte proliferation directly or as a consequence of epidermal barrier impairment. Wood, et al., J Invest Dermatol 1996; 106: 397-403; Blanton, et al., Proc Natl Acad Sci USA 1989; 86: 1273-7. Retinoid-induced stratum corneum compaction (Olsen, et al., supra; Machtinger, et al., supra) is likely related to barrier impairment as stratum corneum thickness is a major determinant of barrier function (Ya-Xian, et al., Arch Dermatol Res 1999; 291: 555-9; de Jongh, et al., Br J Dermatol 2006; 154: 651-7).
Niacin derivatives have been developed for optimal topical delivery of nicotinic acid to skin (Jacobson, et al., Developing Topical Prodrugs for Skin Cancer Prevention. In: Fundamentals of Cancer Prevention (Alberts D S, Hess, Lisa M., ed). Berlin Heidelberg: Springer-Verlag, 2005: 139-60) and have been shown to enhance epidermal differentiation in photodamaged skin, resulting in increased stratum corneum and epidermal thickness and enhanced skin barrier function as assessed by decreased rates of TEWL. Jacobson, et al., Experimental Dermatology, in press. Niacin derivatives are also described in U.S. Pat. Nos. 6,337,065, 6,677,361, 6,750,234 and 6,924,299, each of which is incorporated by reference in its entirety.
One such niacin derivative is myristyl nicotinate, which was developed for optimal topical delivery of nicotinic acid to skin. Myristyl nicotinate has been shown to enhance epidermal differentiation in photodamaged skin, resulting in increased stratum corneum and epidermal thickness and enhanced skin barrier function as assessed by decreased rates of TEWL. Jacobson, et al., Experimental Dermatology, in press.
Hence, it is an object of the present invention to treat the side effects caused by retinoic acid therapy with niacin derivatives. A further feature of the invention is the improvement of skin cell differentiation via use of these niacin derivatives.